Lymphoma patients admitted to the hospital with severe COVID-19 and treated with B-cell depleting immunotherapy within the previous 12 months had nearly twice the risk of prolonged hospitalization and death as those who underwent different treatment, according to a retrospective study involving patients from 16 French hospitals. In all, the study found that about 30 percent of all lymphoma patients hospitalized with severe COVID-19 symptoms died 6 months following admission for their disease.
"Patients with lymphoma may develop immune deficiency due to particular features of their disease or due to their treatment regimen, which can lead to increased incidence and increased severity of infections," said Caroline Besson, MD, PhD, a hematologist at Centre Hospitalier de Versailles and Universite Saint-Quentin-en-Yvelines in France. "In the context of the COVID-19 pandemic, it appeared necessary to analyze the clinical course of this infection in our patients and to characterize the determinants of worse outcomes."
Patients with lymphoma are often treated with B-cell depleting antibodies, such as rituximab or obinutuzumab, that target CD20, a protein found on the surface of B cells. For the past decade or so, this regimen has been shown to improve survival among patients with B-cell non-Hodgkin lymphoma, the most frequent subtype of the disease.
However, these treatments induce rapid B-cell depletion, which alters the generation of antibody responses to new pathogens, which may impact the clinical course of COVID-19, according to Sylvain Lamure, MD, a hematologist with the Centre Hospitalier Universitaire de Montpellier (CHU) in France, who presented the study during the AACR Virtual Meeting: COVID-19 and Cancer.
"Administration of anti-CD20 monoclonal antibody treatment within the last year is one of the main factors associated with a longer in-hospital stay and death from COVID-19," Lamure said. "These conclusions are raising concern about the management of patients requiring anti-CD20 treatment, especially for maintenance treatment."
Research Findings
As outlined in the presentation, Lamure, Besson, and colleagues evaluated data from 111 patients with lymphoma who were admitted to one of 16 French hospitals for severe COVID-19 during March and April of 2020. The researchers specifically focused on identifying factors associated with death from any course and prolonged hospital stay-defined as requiring more than 30 days of hospital stay for COVID-19. For this study, length of hospital stay was considered a proxy for persistent COVID-19.
Data from medical charts was extracted for each patient and included age, sex, body mass index, patient-reported smoking status, past and current co-morbidities, and medications. The most common represented lymphoma subtypes in the study group were 94 cases of B-cell lymphomas, nine with Hodgkin lymphoma and nine with T-cell lymphoma.
After 1 month, 55 patients had recovered from COVID-19, including one who later died from lymphoma after more than 100 days. Some 31 patients were still in the hospital, while one patient experienced persistent symptoms and was later hospitalized. Of the original 111 patients, 24 died after one month.
After a median follow-up of 191 days, the 6-month overall survival in this patient population was 69 percent. Of the 32 with persistent COVID-19, some 19 recovered, four had ongoing symptoms and nine died.
Most of the patients with B-cell lymphomas were treated with anti-CD20 monoclonal antibody combined with bendamustine. Administration of anti-CD20 monoclonal antibody 12 months prior to hospital admission was both associated with decreased overall survival (HR 2.13, 95% Cl 1.03-4.44, p=.043) and prolonged hospital stay (HR 1.97, 95% CI 1.24-3.13, p=0.004)
None of the patients with T-cell lymphoma or classical Hodgkin lymphoma experienced persistent COVID-19; no significant impact was seen for gender, body mass index, smoking status, and medications at baseline.
But patients age 70 and older were more than twice as likely to have a prolonged hospital stay compared to younger patients, and were more than 4 times likely to die. Survival of patients younger than 70 years without relapsed/refractory lymphoma was comparable to that of the general population. Hypertension, previous cancer, use of bendamustine within 12 months before hospital admission, and refractory/relapsed lymphoma were other risk factors.
"Taken together, these data showed that patients with lymphoma hospitalized with COVID-19 have a high risk of death (31%) at 6 months," said Lamure. "Patients with B-cell lymphoma and COVID-19 have a higher incidence of prolonged evolution of SARS-CoV-2 infection."
The results presented during the AACR meeting represent an update from an earlier study published by Lamure, Besson, and colleagues in the October 12, 2020, issue of EClinica Medicine. At that time, the researchers included patients from 12 French hospitals in three French regions, with a brief follow-up of 33 days, and an endpoint of mortality after 30 days.
With the relatively short follow-up in their published study, the researchers did not find any significant risk of prolonged hospitalization or death to patients previously treated with B-cell depleting immunotherapy. Mortality for all lymphoma patients was listed as "comparable to the French COVID-19 population" with "no significant impact of active lymphoma treatment within 1 year," except for bendamustine which was associated with increased mortality.
With the inclusion of more patients and the longer follow-up (median 191 days), "the question of bendamustine remains elusive-a major confounding factor is its used in advanced diseases in France," Lamure said in an interview.
"Remarkably, with longer follow-up, having received anti-CD20 monoclonal antibodies (e.g., rituximab and obinutuzumab) within 1 year before COVID-19 was associated with an increased mortality and longer hospital length of stay," he added.
The team is hypothesizing that previous anti-CD20 does not impact the initial severity of the disease, but that it precludes a patient from developing an efficient immune response against SARS-CoV-2, inducing a longer disease course.
"Colleagues are showing that convalescent plasma may be an option for the persisting form of COVID-19 among the clinic patients and this has to be further assessed," said Lamure. "Questions about the risk of re-infection in the population are unanswered and the response to vaccination needs to be especially assessed in this population."
Warren Froelich is a contributing writer.